Endocrinology and Metabolism

Review Articles

Calcium & bone metabolism
Bone Loss after Solid Organ Transplantation: A Review of Organ-Specific Considerations: Kyoung Jin Kim, Jeonghoon Ha, Sang Wan Kim, Jung-Eun Kim, Sihoon Lee, Han Seok Choi, Namki Hong, Sung Hye Kong, Seong Hee Ahn, So Young Park, Ki-Hyun Baek, on Behalf of Metabolic Bone Disease Study Group of Korean Endocrine Society; Endocrinol Metab. 2024;39(2):267-282. Published online April 25, 2024; DOI: https://doi.org/10.3803/EnM.2024.1939

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Abstract PDF: This review article investigates solid organ transplantation-induced osteoporosis, a critical yet often overlooked issue, emphasizing its significance in post-transplant care. The initial sections provide a comprehensive understanding of the prevalence and multifactorial pathogenesis of transplantation osteoporosis, including factors such as deteriorating post-transplantation health, hormonal changes, and the impact of immunosuppressive medications. Furthermore, the review is dedicated to organ-specific considerations in transplantation osteoporosis, with separate analyses for kidney, liver, heart, and lung transplantations. Each section elucidates the unique challenges and management strategies pertinent to transplantation osteoporosis in relation to each organ type, highlighting the necessity of an organ-specific approach to fully understand the diverse manifestations and implications of transplantation osteoporosis. This review underscores the importance of this topic in transplant medicine, aiming to enhance awareness and knowledge among clinicians and researchers. By comprehensively examining transplantation osteoporosis, this study contributes to the development of improved management and care strategies, ultimately leading to improved patient outcomes in this vulnerable group. This detailed review serves as an essential resource for those involved in the complex multidisciplinary care of transplant recipients.

Calcium & bone metabolism
Acromegaly and Bone: An Update: Andrea Giustina; Endocrinol Metab. 2023;38(6):655-666. Published online December 22, 2023; DOI: https://doi.org/10.3803/EnM.2023.601

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Since our discovery in 2006 that acromegaly is associated with an increased risk of vertebral fractures, many authors have confirmed this finding in both cross-sectional and prospective studies. Due to the high epidemiological and clinical impact of this newly discovered comorbidity of acromegaly, this topic has progressively become more important and prominent over the years, and the pertinent literature has been enriched by new findings on the pathophysiology and treatment. The aim of this narrative review was to discuss these novel findings, integrating them with the seminal observations, in order to give the reader an updated view of how the field of acromegaly and bone is developing, from strong clinical observations to a mechanistic understanding and possible prevention and treatment.

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New insights into the vitamin D/PTH axis in endocrine-driven metabolic bone diseases
Luigi di Filippo, John P. Bilezikian, Ernesto Canalis, Umberto Terenzi, Andrea Giustina
Endocrine.2024;[Epub] CrossRef

Original Articles

Calcium & bone metabolism Big Data Articles (National Health Insurance Service Database)
Association between Smoking Status and the Risk of Hip Fracture in Patients with Type 2 Diabetes: A Nationwide Population-Based Study: Se-Won Lee, Jun-Young Heu, Ju-Yeong Kim, Jinyoung Kim, Kyungdo Han, Hyuk-Sang Kwon; Endocrinol Metab. 2023;38(6):679-689. Published online December 6, 2023; DOI: https://doi.org/10.3803/EnM.2023.1760

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Abstract PDF Supplementary Material PubReader ePub: Background
Limited longitudinal evidence exists regarding the potential association between smoking status and hip fracture among individuals with type 2 diabetes. We investigated this association using large-scale, nationwide cohort data for the Korean population.
Methods
This nationwide cohort study included 1,414,635 adults aged 40 and older who received Korean National Health Insurance Service health examinations between 2009 and 2012. Subjects with type 2 diabetes were categorized according to their smoking status, amount smoked (pack-years), number of cigarettes smoked per day, and duration of smoking. The results are presented as hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between smoking status parameters and risk of hip fracture in multivariable Cox proportional hazard regression analysis.
Results
Compared with never-smokers, an increased adjusted HR (aHR) for hip fracture was observed in current smokers (1.681; 95% CI, 1.578 to 1.791), and a comparable aHR for hip fracture was found in former smokers (1.065; 95% CI, 0.999 to 1.136). For former smokers who had smoked 20 pack-years or more, the risk was slightly higher than that for never-smokers (aHR, 1.107; 95% CI, 1.024 to 1.196). The hip fracture risk of female former smokers was similar to that of female current smokers, but the hip fracture risk in male former smokers was similar to that of male never-smokers.
Conclusion
Smoking is associated with an increased risk of hip fracture in patients with type 2 diabetes. Current smokers with diabetes should be encouraged to quit smoking because the risk of hip fracture is greatly reduced in former smokers.

Calcium & bone metabolism Big Data Articles (National Health Insurance Service Database)
Increased Risk of Hip Fracture in Patients with Acromegaly: A Nationwide Cohort Study in Korea: Jiwon Kim, Namki Hong, Jimi Choi, Ju Hyung Moon, Eui Hyun Kim, Eun Jig Lee, Sin Gon Kim, Cheol Ryong Ku; Endocrinol Metab. 2023;38(6):690-700. Published online October 30, 2023; DOI: https://doi.org/10.3803/EnM.2023.1782

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Abstract PDF Supplementary Material PubReader ePub: Background
Acromegaly leads to various skeletal complications, and fragility fractures are emerging as a new concern in patients with acromegaly. Therefore, this study investigated the risk of fractures in Korean patients with acromegaly.
Methods
We used the Korean nationwide claims database from 2009 to 2019. A total of 931 patients with acromegaly who had never used an osteoporosis drug before and were treated with surgery alone were selected as study participants, and a 1:29 ratio of 26,999 age- and sex-matched osteoporosis drug-naïve controls without acromegaly were randomly selected from the database.
Results
The mean age was 46.2 years, and 50.0% were male. During a median follow-up of 54.1 months, there was no difference in the risks of all, vertebral, and non-vertebral fractures between the acromegaly and control groups. However, hip fracture risk was significantly higher (hazard ratio [HR], 2.73; 95% confidence interval [CI], 1.32 to 5.65), and non-hip and non-vertebral fractures risk was significantly lower (HR, 0.40; 95% CI, 0.17 to 0.98) in patients with acromegaly than in controls; these results remained robust even after adjustment for socioeconomic status and baseline comorbidities. Age, type 2 diabetes mellitus, cardio-cerebrovascular disease, fracture history, recent use of acid-suppressant medication, psychotropic medication, and opioids were risk factors for all fractures in patients with acromegaly (all P<0.05).
Conclusion
Compared with controls, patients surgically treated for acromegaly had a higher risk of hip fractures. The risk factors for fracture in patients with acromegaly were consistent with widely accepted risk factors in the general population.

Calcium & bone metabolism
Age-Dependent Association of Height Loss with Incident Fracture Risk in Postmenopausal Korean Women: Chaewon Lee, Hye-Sun Park, Yumie Rhee, Namki Hong; Endocrinol Metab. 2023;38(6):669-678. Published online September 1, 2023; DOI: https://doi.org/10.3803/EnM.2023.1734

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Abstract PDF Supplementary Material PubReader ePub: Background
Height loss is a simple clinical measure associated with increased fracture risk. However, limited data exists on the association between height loss and fracture risk in postmenopausal Korean women. It is unknown whether this association varies with age.
Methods
Data on height loss over a 6-year period were collected from a community-based longitudinal follow-up cohort (Ansung cohort of the Korean Genome and Epidemiology Study). Incident fractures were defined based on self-reported fractures after excluding those due to severe trauma or toes/fingers. The association between incident fractures and height loss was investigated using a Cox proportional hazards model.
Results
During a median follow-up of 10 years after the second visit, 259/1,806 participants (median age, 64 years) experienced incident fractures. Overall, a 1 standard deviation (SD) decrease in height (1.6 cm/median 5.8 years) was associated with 9% increased risk of fracture (hazard ratio [HR], 1.09; P=0.037), which lost statistical significance after adjustment for covariates. When stratified into age groups (50–59, 60–69, 70 years or older), a 1 SD decrease in height remained a robust predictor of fracture in the 50 to 59 years age group after adjusting for covariates (adjusted hazard ratio [aHR], 1.52; P=0.003), whereas height loss was not an independent predictor of fracture in the 60 to 69 (aHR, 1.06; P=0.333) or the 70 years or older age groups (aHR, 1.05; P=0.700; P for interaction <0.05, for all).
Conclusion
Height loss during the previous 6 years was associated with an increased 10-year fracture risk in postmenopausal women in their 50s.

Review Articles

Calcium & bone metabolism
Skeletal Senescence with Aging and Type 2 Diabetes: Joshua Nicholas Farr; Endocrinol Metab. 2023;38(3):295-301. Published online June 14, 2023; DOI: https://doi.org/10.3803/EnM.2023.1727

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Osteoporosis and type 2 diabetes (T2D) are common diseases that often coexist. While both of these diseases are associated with poor bone quality and increased fracture risk, their pathogenesis of increased fracture risk differs and is multifactorial. Mounting evidence now indicates that key fundamental mechanisms that are central to both aging and energy metabolism exist. Importantly, these mechanisms represent potentially modifiable therapeutic targets for interventions that could prevent or alleviate multiple complications of osteoporosis and T2D, including poor bone quality. One such mechanism that has gained increasing momentum is senescence, which is a cell fate that contributes to multiple chronic diseases. Accumulating evidence has established that numerous boneresident cell types become susceptible to cellular senescence with old age. Recent work also demonstrates that T2D causes the premature accumulation of senescent osteocytes during young adulthood, at least in mice, although it remains to be seen which other bone-resident cell types become senescent with T2D. Given that therapeutically removing senescent cells can alleviate age-related bone loss and T2D-induced metabolic dysfunction, it will be important in future studies to rigorously test whether interventions that eliminate senescent cells can also alleviate skeletal dysfunction in context of T2D, as it does with aging.

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Single-cell sequencing reveals an important role of SPP1 and microglial activation in age-related macular degeneration
Shizhen Lei, Mang Hu, Zhongtao Wei
Frontiers in Cellular Neuroscience.2024;[Epub] CrossRef
The synergistic effect of diabetes mellitus and osteoporosis on the all-cause mortality: a cohort study of an American population
Weihua Li, Siyu Xie, Shengdong Zhong, Liting Lan
Frontiers in Endocrinology.2024;[Epub] CrossRef
Identification of systemic biomarkers and potential drug targets for age-related macular degeneration
Shizhen Lei, Mang Hu, Zhongtao Wei
Frontiers in Aging Neuroscience.2024;[Epub] CrossRef

Calcium & bone metabolism
Cardiovascular Impact of Calcium and Vitamin D Supplements: A Narrative Review: Fatima Zarzour, Ahmad Didi, Mohammed Almohaya, David Kendler; Endocrinol Metab. 2023;38(1):56-68. Published online February 16, 2023; DOI: https://doi.org/10.3803/EnM.2022.1644

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Calcium and vitamin D play an important role in mineral homeostasis and the maintenance of skeletal health. Calcium and vitamin D supplements have been widely used for fracture prevention in elderly populations. Many trials have studied the effectiveness and cardiovascular safety of calcium and vitamin D supplementation, with disparate results. In this review, we summarize the most important trials and systematic reviews. There is significant heterogeneity in clinical trial design, differences in the nature of trial outcomes (self-reported vs. verified), prior calcium intake, and trial size. Inconsistent results have been reported concerning the effects of calcium and vitamin D supplementation on cardiovascular outcomes. Most current guidelines recommend calcium intake of up to 1,200 mg daily, preferably from the diet, without concern for cardiovascular risk. Recommendations regarding vitamin D supplementation vary widely. There is compelling evidence from well-conducted randomized trials that modest vitamin D supplementation is safe but does not confer cardiovascular benefit or cardiovascular harm.

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Evaluating adherence, tolerability and safety of oral calcium citrate in elderly osteopenic subjects: a real-life non-interventional, prospective, multicenter study
Mariangela Rondanelli, Salvatore Minisola, Marco Barale, Daniele Barbaro, Francesca Mansueto, Santina Battaglia, Gloria Bonaccorsi, Santina Caliri, Alessandro Cavioni, Luciano Colangelo, Sabrina Corbetta, Federica Coretti, Giorgia Dito, Valentina Gavioli,
Aging Clinical and Experimental Research.2024;[Epub] CrossRef
Association between Daily Dietary Calcium Intake and the Risk of Cardiovascular Disease (CVD) in Postmenopausal Korean Women
Jae Kyung Lee, Thi Minh Chau Tran, Euna Choi, Jinkyung Baek, Hae-Rim Kim, Heeyon Kim, Bo Hyon Yun, Seok Kyo Seo
Nutrients.2024; 16(7): 1043. CrossRef
Effect of Denosumab on Bone Density in Postmenopausal Osteoporosis: A Comparison with and without Calcium Supplementation in Patients on Standard Diets in Korea
Chaiho Jeong, Jinyoung Kim, Jeongmin Lee, Yejee Lim, Dong-Jun Lim, Ki-Hyun Baek, Jeonghoon Ha
Journal of Clinical Medicine.2023; 12(21): 6904. CrossRef

Original Article

Calcium & Bone Metabolism
Development of a Spine X-Ray-Based Fracture Prediction Model Using a Deep Learning Algorithm: Sung Hye Kong, Jae-Won Lee, Byeong Uk Bae, Jin Kyeong Sung, Kyu Hwan Jung, Jung Hee Kim, Chan Soo Shin; Endocrinol Metab. 2022;37(4):674-683. Published online August 5, 2022; DOI: https://doi.org/10.3803/EnM.2022.1461

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Background
Since image-based fracture prediction models using deep learning are lacking, we aimed to develop an X-ray-based fracture prediction model using deep learning with longitudinal data.
Methods
This study included 1,595 participants aged 50 to 75 years with at least two lumbosacral radiographs without baseline fractures from 2010 to 2015 at Seoul National University Hospital. Positive and negative cases were defined according to whether vertebral fractures developed during follow-up. The cases were divided into training (n=1,416) and test (n=179) sets. A convolutional neural network (CNN)-based prediction algorithm, DeepSurv, was trained with images and baseline clinical information (age, sex, body mass index, glucocorticoid use, and secondary osteoporosis). The concordance index (C-index) was used to compare performance between DeepSurv and the Fracture Risk Assessment Tool (FRAX) and Cox proportional hazard (CoxPH) models.
Results
Of the total participants, 1,188 (74.4%) were women, and the mean age was 60.5 years. During a mean follow-up period of 40.7 months, vertebral fractures occurred in 7.5% (120/1,595) of participants. In the test set, when DeepSurv learned with images and clinical features, it showed higher performance than FRAX and CoxPH in terms of C-index values (DeepSurv, 0.612; 95% confidence interval [CI], 0.571 to 0.653; FRAX, 0.547; CoxPH, 0.594; 95% CI, 0.552 to 0.555). Notably, the DeepSurv method without clinical features had a higher C-index (0.614; 95% CI, 0.572 to 0.656) than that of FRAX in women.
Conclusion
DeepSurv, a CNN-based prediction algorithm using baseline image and clinical information, outperformed the FRAX and CoxPH models in predicting osteoporotic fracture from spine radiographs in a longitudinal cohort.

Citations

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Automated detection of vertebral fractures from X-ray images: A novel machine learning model and survey of the field
Li-Wei Cheng, Hsin-Hung Chou, Yu-Xuan Cai, Kuo-Yuan Huang, Chin-Chiang Hsieh, Po-Lun Chu, I-Szu Cheng, Sun-Yuan Hsieh
Neurocomputing.2024; 566: 126946. CrossRef
Application of radiomics model based on lumbar computed tomography in diagnosis of elderly osteoporosis
Baisen Chen, Jiaming Cui, Chaochen Li, Pengjun Xu, Guanhua Xu, Jiawei Jiang, Pengfei Xue, Yuyu Sun, Zhiming Cui
Journal of Orthopaedic Research.2024;[Epub] CrossRef
Machine Learning and Deep Learning in Spinal Injury: A Narrative Review of Algorithms in Diagnosis and Prognosis
Satoshi Maki, Takeo Furuya, Masahiro Inoue, Yasuhiro Shiga, Kazuhide Inage, Yawara Eguchi, Sumihisa Orita, Seiji Ohtori
Journal of Clinical Medicine.2024; 13(3): 705. CrossRef
A CT-based Deep Learning Model for Predicting Subsequent Fracture Risk in Patients with Hip Fracture
Yisak Kim, Young-Gon Kim, Jung-Wee Park, Byung Woo Kim, Youmin Shin, Sung Hye Kong, Jung Hee Kim, Young-Kyun Lee, Sang Wan Kim, Chan Soo Shin
Radiology.2024;[Epub] CrossRef
A Novel QCT-Based Deep Transfer Learning Approach for Predicting Stiffness Tensor of Trabecular Bone Cubes
Pengwei Xiao, Tinghe Zhang, Yufei Huang, Xiaodu Wang
IRBM.2024; 45(2): 100831. CrossRef
Deep learning in the radiologic diagnosis of osteoporosis: a literature review
Yu He, Jiaxi Lin, Shiqi Zhu, Jinzhou Zhu, Zhonghua Xu
Journal of International Medical Research.2024;[Epub] CrossRef
Development and Validation of a Convolutional Neural Network Model to Predict a Pathologic Fracture in the Proximal Femur Using Abdomen and Pelvis CT Images of Patients With Advanced Cancer
Min Wook Joo, Taehoon Ko, Min Seob Kim, Yong-Suk Lee, Seung Han Shin, Yang-Guk Chung, Hong Kwon Lee
Clinical Orthopaedics & Related Research.2023; 481(11): 2247. CrossRef
Automated Opportunistic Trabecular Volumetric Bone Mineral Density Extraction Outperforms Manual Measurements for the Prediction of Vertebral Fractures in Routine CT
Sophia S. Goller, Jon F. Rischewski, Thomas Liebig, Jens Ricke, Sebastian Siller, Vanessa F. Schmidt, Robert Stahl, Julian Kulozik, Thomas Baum, Jan S. Kirschke, Sarah C. Foreman, Alexandra S. Gersing
Diagnostics.2023; 13(12): 2119. CrossRef
Machine learning‐based prediction of osteoporosis in postmenopausal women with clinical examined features: A quantitative clinical study
Kainat A. Ullah, Faisal Rehman, Muhammad Anwar, Muhammad Faheem, Naveed Riaz
Health Science Reports.2023;[Epub] CrossRef
Skeletal Fracture Detection with Deep Learning: A Comprehensive Review
Zhihao Su, Afzan Adam, Mohammad Faidzul Nasrudin, Masri Ayob, Gauthamen Punganan
Diagnostics.2023; 13(20): 3245. CrossRef
Deep learning system for automated detection of posterior ligamentous complex injury in patients with thoracolumbar fracture on MRI
Sang Won Jo, Eun Kyung Khil, Kyoung Yeon Lee, Il Choi, Yu Sung Yoon, Jang Gyu Cha, Jae Hyeok Lee, Hyunggi Kim, Sun Yeop Lee
Scientific Reports.2023;[Epub] CrossRef
Vertebra Segmentation Based Vertebral Compression Fracture Determination from Reconstructed Spine X-Ray Images
Srinivasa Rao Gadu, Chandra Sekhar Potala
International Journal of Electrical and Electronics Research.2023; 11(4): 1225. CrossRef
Computer Vision in Osteoporotic Vertebral Fracture Risk Prediction: A Systematic Review
Anthony K. Allam, Adrish Anand, Alex R. Flores, Alexander E. Ropper
Neurospine.2023; 20(4): 1112. CrossRef
A Meaningful Journey to Predict Fractures with Deep Learning
Jeonghoon Ha
Endocrinology and Metabolism.2022; 37(4): 617. CrossRef
New Horizons: Artificial Intelligence Tools for Managing Osteoporosis
Hans Peter Dimai
The Journal of Clinical Endocrinology & Metabolism.2022;[Epub] CrossRef

Review Article

Adrenal Gland
Long-Term Outcomes of Congenital Adrenal Hyperplasia: Anna Nordenström, Svetlana Lajic, Henrik Falhammar; Endocrinol Metab. 2022;37(4):587-598. Published online July 8, 2022; DOI: https://doi.org/10.3803/EnM.2022.1528

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A plethora of negative long-term outcomes have been associated with congenital adrenal hyperplasia (CAH). The causes are multiple and involve supra-physiological gluco- and mineralocorticoid replacement, excess adrenal androgens both intrauterine and postnatal, elevated steroid precursor and adrenocorticotropic hormone levels, living with a congenital condition as well as the proximity of the cytochrome P450 family 21 subfamily A member 2 (CYP21A2) gene to other genes. This review aims to discuss the different long-term outcomes of CAH.

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Increased Prevalence of Accidents and Injuries in Congenital Adrenal Hyperplasia: A Population-based Cohort Study
Henrik Falhammar, Angelica Lindén Hirschberg, Agneta Nordenskjöld, Henrik Larsson, Anna Nordenström
The Journal of Clinical Endocrinology & Metabolism.2024; 109(3): e1175. CrossRef
International Newborn Screening Practices for the Early Detection of Congenital Adrenal Hyperplasia
Tracey A. Conlon, Colin P. Hawkes, Jennifer J. Brady, J. Gerard Loeber, Nuala Murphy
Hormone Research in Paediatrics.2024; 97(2): 113. CrossRef
Low renin forms of monogenic hypertension: review of the evidence
Ugochi Chinenye Okorafor, Uchechi Chioma Okorafor
Journal of Clinical Medicine of Kazakhstan.2024; 21(1): 14. CrossRef
Increased risk of nephrolithiasis: an emerging issue in children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Mariangela Chiarito, Crescenza Lattanzio, Vito D’Ascanio, Donatella Capalbo, Paolo Cavarzere, Anna Grandone, Francesca Aiello, Giorgia Pepe, Malgorzata Wasniewska, Thomas Zoller, Mariacarolina Salerno, Maria Felicia Faienza
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Congenital adrenal hyperplasia: New biomarkers and adult treatments
Bleuenn Dreves, Yves Reznik, Antoine Tabarin
Annales d'Endocrinologie.2023; 84(4): 472. CrossRef
Interpretation of Steroid Biomarkers in 21-Hydroxylase Deficiency and Their Use in Disease Management
Kyriakie Sarafoglou, Deborah P Merke, Nicole Reisch, Hedi Claahsen-van der Grinten, Henrik Falhammar, Richard J Auchus
The Journal of Clinical Endocrinology & Metabolism.2023; 108(9): 2154. CrossRef
Impact of Newborn Screening on Adult Height in Patients With Congenital Adrenal Hyperplasia (CAH)
Heike Hoyer-Kuhn, Alexander J Eckert, Gerhard Binder, Walter Bonfig, Angelika Dübbers, Stefan Riedl, Joachim Woelfle, Helmuth G Dörr, Reinhard W Holl
The Journal of Clinical Endocrinology & Metabolism.2023; 108(11): e1199. CrossRef
Specialty grand challenge in adrenal endocrinology
Henrik Falhammar
Frontiers in Endocrinology.2023;[Epub] CrossRef
Contexts of care for people with differences of sex development
Alexandra E. Kulle, Martina Jürgensen, Ulla Döhnert, Lisa Malich, Louise Marshall, Olaf Hiort
Medizinische Genetik.2023; 35(3): 181. CrossRef
Cardiovascular risk in Cuban adolescents and young adults with congenital adrenal hyperplasia
Tania M. Espinosa Reyes, Alba Katherine Pesántez Velepucha, Julio Oscar Cabrera Rego, Wendy Valdés Gómez, Emma Domínguez Alonso, Henrik Falhammar
BMC Endocrine Disorders.2023;[Epub] CrossRef
Landscape of Adrenal Tumours in Patients with Congenital Adrenal Hyperplasia
Mara Carsote, Ana-Maria Gheorghe, Claudiu Nistor, Alexandra-Ioana Trandafir, Oana-Claudia Sima, Anca-Pati Cucu, Adrian Ciuche, Eugenia Petrova, Adina Ghemigian
Biomedicines.2023; 11(11): 3081. CrossRef
Editorial: Recent advances in diagnosis and treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Semra Çaglar Çetinkaya
Frontiers in Endocrinology.2023;[Epub] CrossRef
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Andreea Gabriela Nicola, Mara Carsote, Ana-Maria Gheorghe, Eugenia Petrova, Alexandru Dan Popescu, Adela Nicoleta Staicu, Mihaela Jana Țuculină, Cristian Petcu, Ionela Teodora Dascălu, Tiberiu Tircă
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Original Article

Calcium & Bone Metabolism
Effect of Vitamin D Supplementation on Risk of Fractures and Falls According to Dosage and Interval: A Meta-Analysis: Sung Hye Kong, Han Na Jang, Jung Hee Kim, Sang Wan Kim, Chan Soo Shin; Endocrinol Metab. 2022;37(2):344-358. Published online April 25, 2022; DOI: https://doi.org/10.3803/EnM.2021.1374

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Background
Although recent studies comparing various dosages and intervals of vitamin D supplementation have been published, it is yet to be elucidated whether there is an appropriate dose or interval to provide benefit regarding fracture risk. We aimed to assess the published evidence available to date regarding the putative beneficial effects of vitamin D supplements on fractures and falls according to various dosages and intervals.
Methods
We performed a meta-analysis of randomized controlled studies reporting associations between vitamin D supplementation and the risks of fractures and falls in PubMed, EMBASE, and Cochrane library. Studies with supplements of ergocalciferol or calcitriol, those with a number of event ≤10, or those with a follow-up duration of less than 6 months were also excluded.
Results
Thirty-two studies were included in the final analysis. Vitamin D supplementation with daily dose of 800 to 1,000 mg was associated with lower risks of osteoporotic fracture and fall (pooled relative risk [RR], 0.87; 95% confidence interval [CI], 0.78 to 0.97 and RR, 0.91; 95% CI, 0.85 to 0.98), while studies with <800 or >1,000 mg/day did not. Also, among intervals, daily administration of vitamin D was associated with the reduced risk of falls, while intermittent dose was not. Also, patients with vitamin D deficiency showed a significant risk reduction of falls after vitamin D supplementation.
Conclusion
Daily vitamin D dose of 800 to 1,000 IU was the most probable way to reduce the fracture and fall risk. Further studies designed with various regimens and targeted vitamin D levels are required to elucidate the benefits of vitamin D supplements.

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Ukrainian Consensus on Diagnosis and Management of Vitamin D Deficiency in Adults
Nataliia Grygorieva, Mykola Tronko, Volodymir Kovalenko, Serhiy Komisarenko, Tetiana Tatarchuk, Ninel Dedukh, Mykola Veliky, Serhiy Strafun, Yulia Komisarenko, Andrii Kalashnikov, Valeria Orlenko, Volodymyr Pankiv, Oleg Shvets, Inna Gogunska, Svitlana Reg
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Lamia Aldhbiban, Fai Alhoshan, Raghad Alomari, Shahad A Almatrafi, Yousef Alanazi, Samir Alsayegh, Haifa Y Alfaraidi, Ayman H Jawadi, Fahad N Aljuraibah
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Nikhil Gupta, Navjot Kanwar, Anchal Arora, Kavin Khatri, Abhinav Kanwal
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A.E. Smit, O.C. Meijer, E.M. Winter
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Vitamin D Deficiency in Patients With Low-Energy Hip Fractures in Accordance With the Mediterranean Paradox
Christos Konstantinidis, Ourania Psoma, Christos Kotsias, Vasileios Panagiotopoulos , Sotiris Plakoutsis, Dimitrios Tsiampas, Dimitrios Vardakas, Dimitrios Giotis
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Lingfang He, Tianqi Ma, Guogang Zhang, Xunjie Cheng, Yongping Bai
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Vitamin D and Calcium in Osteoporosis, and the Role of Bone Turnover Markers: A Narrative Review of Recent Data from RCTs
Gavriela Voulgaridou, Sousana K. Papadopoulou, Paraskevi Detopoulou, Despoina Tsoumana, Constantinos Giaginis, Foivi S. Kondyli, Evgenia Lymperaki, Agathi Pritsa
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Recent advances in the identification of related factors and preventive strategies of hip fracture
Yaohui Yu, Yudan Wang, Xiaoli Hou, Faming Tian
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Can Nutrition Contribute to a Reduction in Sarcopenia, Frailty, and Comorbidities in a Super-Aged Society?
Sadao Yoshida, Ryo Shiraishi, Yuki Nakayama, Yasuko Taira
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Safety Profile of Vitamin D in Italy: An Analysis of Spontaneous Reports of Adverse Reactions Related to Drugs and Food Supplements
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Review Article

Calcium & Bone Metabolism
Discontinuing Denosumab: Can It Be Done Safely? A Review of the Literature: Wei Lin Tay, Donovan Tay; Endocrinol Metab. 2022;37(2):183-194. Published online April 14, 2022; DOI: https://doi.org/10.3803/EnM.2021.1369

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Denosumab, which has been approved for the treatment of osteoporosis since 2010, is a fully humanised monoclonal antibody against a cytokine, receptor activator of nuclear factor kappa B ligand (RANKL), involved in bone resorption. Continued use of denosumab results in a potent and sustained decrease in bone turnover, an increase in bone mineral density (BMD), and a reduction in vertebral and hip fractures. The anti-resorptive effects of denosumab are reversible upon cessation, and this reversal is accompanied by a transient marked increase in bone turnover that is associated with bone loss, and of concern, an increased risk of multiple vertebral fractures. In this review, we outline the effects of denosumab withdrawal on bone turnover markers, BMD, histomorphometry, and fracture risk. We provide an update on recent clinical trials that sought to answer how clinicians can transition away from denosumab safely with follow-on therapy to mitigate bone loss and summarise the recommendations of various international guidelines.

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Loss of lower extremity bone mineral density 1 year after denosumab is discontinued in persons with subacute spinal cord injury
Christopher M. Cirnigliaro, Michael F. La Fountaine, J. Scott Parrott, Steven C. Kirshblum, Susan J. Sauer, Sue A. Shapses, Isa A. McClure, William A. Bauman
Osteoporosis International.2023; 34(4): 741. CrossRef
Persistence with Denosumab in Male Osteoporosis Patients: A Real-World, Non-Interventional Multicenter Study
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Endocrinology and Metabolism.2023; 38(2): 260. CrossRef

Original Articles

Calcium & Bone Metabolism Big Data Articles (National Health Insurance Service Database)
Hip Fracture Risk According to Diabetic Kidney Disease Phenotype in a Korean Population: Seung Eun Lee, Juhwan Yoo, Kyoung-Ah Kim, Kyungdo Han, Han Seok Choi; Endocrinol Metab. 2022;37(1):148-158. Published online February 28, 2022; DOI: https://doi.org/10.3803/EnM.2021.1315

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Background
Diabetic kidney disease (DKD) is associated with an elevated risk of fractures. However, little is known about the association between proteinuric or non-proteinuric DKD and the risk of hip fracture. Thus, we investigated the incidence of hip fractures among Korean adults with type 2 diabetes mellitus (T2DM) stratified by DKD phenotype.
Methods
In this retrospective cohort study using the Korean National Health Insurance Service database, patients with T2DM who received at least one general health checkup between 2009 and 2012 were followed until the date of hip fracture, death, or December 31, 2018. We classified the DKD phenotype by proteinuria and estimated glomerular filtration rate (eGFR), as follows: no DKD (PU⁻GFR⁻), proteinuric DKD with normal eGFR (PU⁺GFR⁻), non-proteinuric DKD with reduced eGFR (PU⁻GFR⁺), and proteinuric DKD with reduced eGFR (PU⁺GFR⁺)
Results
The cumulative incidence of hip fractures was highest in the PU⁺GFR⁺ group, followed by the PU⁻GFR⁺ group and the PU⁺GFR⁻ group. After adjustment for confounding factors, the hazard ratio (HR) for hip fracture was still highest in the PU⁺GFR⁺ group. However, the PU⁺GFR⁻ group had a higher HR for hip fracture than the PU⁻GFR⁺ group (PU⁺GFR⁺ : HR, 1.69; 95% confidence interval [CI], 1.57 to 1.81; PU⁺GFR⁻ : HR, 1.37; 95% CI, 1.30 to 1.46; PU⁻GFR⁺ : HR, 1.20; 95% CI, 1.16 to 1.24 using the PU⁻GFR⁻ group as the reference category).
Conclusion
The present study demonstrated that DKD was significantly associated with a higher risk of hip fracture, with proteinuria as a major determinant.

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Proteinuria screening and risk of bone fracture: a retrospective cohort study using a nationwide population-based database
Akira Okada, Akira Honda, Hideaki Watanabe, Yusuke Sasabuchi, Shotaro Aso, Kayo Ikeda Kurakawa, Masaomi Nangaku, Toshimasa Yamauchi, Hideo Yasunaga, Hirotaka Chikuda, Takashi Kadowaki, Satoko Yamaguchi
Clinical Kidney Journal.2024;[Epub] CrossRef
Fracture risks associated with sodium-glucose cotransporter-2 inhibitors in type 2 diabetes patients across eGFR and albuminuria categories: A population-based study in Hong Kong
David Tak Wai Lui, Tingting Wu, Eric Ho Man Tang, Ivan Chi Ho Au, Chi Ho Lee, Yu Cho Woo, Kathryn Choon Beng Tan, Carlos King Ho Wong
Diabetes Research and Clinical Practice.2023; 197: 110576. CrossRef
Diagnose und Management der Osteoporose bei Diabetes mellitus (Update 2023)
Christian Muschitz, Alexandra Kautzky-Willer, Yvonne Winhofer, Martina Rauner, Judith Haschka, Daniel Cejka, Robert Wakolbinger-Habel, Peter Pietschmann
Wiener klinische Wochenschrift.2023; 135(S1): 207. CrossRef
Association between exercise and risk of fractures in new-onset type 2 diabetes: a retrospective cohort study
Seung Eun Lee, Juhwan Yoo, Bong-Seong Kim, Kyoung-Ah Kim, Kyungdo Han, Han Seok Choi
Archives of Osteoporosis.2023;[Epub] CrossRef
Two-Year Changes in Diabetic Kidney Disease Phenotype and the Risk of Heart Failure: A Nationwide Population-Based Study in Korea
Seung Eun Lee, Juhwan Yoo, Han Seok Choi, Kyungdo Han, Kyoung-Ah Kim
Diabetes & Metabolism Journal.2023; 47(4): 523. CrossRef

Calcium & Bone Metabolism Big Data Articles (National Health Insurance Service Database)
10-Year Fracture Risk in Postmenopausal Women with Osteopenia and Osteoporosis in South Korea: Yeon-Hee Baek, Sun Wook Cho, Han Eol Jeong, Ju Hwan Kim, Yunji Hwang, Jeffrey L. Lange, Ju-Young Shin; Endocrinol Metab. 2021;36(6):1178-1188. Published online December 16, 2021; DOI: https://doi.org/10.3803/EnM.2021.1215

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Background
In South Korea, women aged 66 years are eligible for complimentary bone mineral density (BMD) screening via the National Screening Program for Transitional Ages. We aimed to evaluate the 10-year fracture risk in women receiving BMD screening between January 2008 and December 2015.
Methods
BMD was classified as normal (T-score ≥–1.0 standard deviation [SD]), osteopenia (T-score <–1.0 SD and >–2.5 SD), and osteoporosis (T score ≤–2.5 SD) from dual-energy X-ray absorptiometry. Follow-up continued from the screening date until a diagnosis for clinical fragility fracture (including sites of the vertebrae, hip, pelvis, clavicle, humerus, forearm, wrist, lower leg, and ankle), censored at the earliest date of trauma, death, or December 2017; fracture was ascertained using diagnostic codes from the National Health Insurance Service database. A multivariable Cox proportional hazard model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of fracture in women with osteopenia or osteoporosis relative to women with normal BMD.
Results
Among the 271,197 women screened, 44.0% had osteopenia and 35.2% had osteoporosis. The 10 year cumulative incidence of fragility fractures was 31.1%, 37.5%, and 44.3% in women with normal BMD, osteopenia, and osteoporosis, respectively. Fracture risk was higher in women with osteopenia (HR, 1.31; 95% CI, 1.28 to 1.34) and osteoporosis (HR, 1.68; 95% CI, 1.64 to 1.72) than in women with normal BMD.
Conclusion
Women with osteopenia and women with osteoporosis, identified by the national BMD screening program, demonstrated a substantially elevated risk of fracture.

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Understanding the long-term impact of incident osteoporotic fractures on healthcare utilization and costs in Korean postmenopausal women
S. Han, S. Kim, E.J. Yeh, H.S. Suh
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Duration of osteoporosis treatment to reduce the risk of subsequent osteoporotic fracture and all-cause mortality in elderly hip fracture patients in a Korean real-world study
Soong Joon Lee, Minjoon Cho, Hojoon Lee, Hyuna Lim, Jae Hyup Lee
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Sung Hye Kong, Ae Jeong Jo, Chan Mi Park, Kyun Ik Park, Ji Eun Yun, Jung Hee Kim
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ACS Biomaterials Science & Engineering.2023; 9(6): 3435. CrossRef
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Menopause.2023; 30(11): 1139. CrossRef
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Chaewon Lee, Hye-Sun Park, Yumie Rhee, Namki Hong
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Jeonghoon Ha
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Kyung Wook Kim, Young Il Kim, Ki-Choul Kim
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Yihui Zhang, Yilihamu Dilixiati, Wei Jiang, Xiufeng Cao, Yuanyuan Chen, Hui Guo, Christian-Heinz Anderwald
International Journal of Endocrinology.2022; 2022: 1. CrossRef

Review Article

Bone Metabolism
Operationalizing Treat-to-Target for Osteoporosis: E. Michael Lewiecki; Endocrinol Metab. 2021;36(2):270-278. Published online March 24, 2021; DOI: https://doi.org/10.3803/EnM.2021.970

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Treat-to-target (TTT) for osteoporosis is a concept for individualizing patient treatment decisions that focuses on achieving an acceptable level of fracture risk rather than response to treatment alone. While a response to treatment is essential in order to achieve an acceptable level of risk, it is not necessarily sufficient. Some patients have a good response to treatment yet remain at high level of fracture risk. Since there is no way to directly measure bone strength in patients treated for osteoporosis, a surrogate measurement must be used. Bone mineral density (BMD) is commonly used to select patients for treatment and has emerged as the most useful surrogate for assessing reduction of fracture risk after treatment is started. Recent large meta-regression studies have shown a robust correlation between larger increases in BMD with treatment and greater reductions in fracture risk. Application of TTT for osteoporosis involves assessing fracture risk before starting treatment and initiating treatment with an agent that is most likely to reduce fracture risk to an acceptable level, represented by a target BMD T-score, over a reasonable period of time. This review offers suggestions for implementing TTT for osteoporosis in clinical practice and managing patients who fail or succeed in reaching the target. More study is needed to fully validate the use of TTT for osteoporosis for initiating and modifying treatments to reduce fracture risk.

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Treatment sequencing using the dual amylin and calcitonin receptor agonist KBP-336 and semaglutide results in durable weight loss
Anna Thorsø Larsen, Morten A. Karsdal, Kim Henriksen
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Original Article

Clinical Study
Effects of Systemic Glucocorticoid Use on Fracture Risk: A Population-Based Study: Ji Weon Koh, Junkang Kim, Hyemin Cho, Yong-Chan Ha, Tae-Young Kim, Young-Kyun Lee, Ha Young Kim, Sunmee Jang; Endocrinol Metab. 2020;35(3):562-570. Published online September 22, 2020; DOI: https://doi.org/10.3803/EnM.2020.659

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Background
Long-term glucocorticoid use increases fracture risk by reducing bone mass. This study evaluated the relationship between hip and vertebral fractures and the total amount of systematic glucocorticoid use.
Methods
We randomly selected 1,896,159 people aged 20 to 100 years who participated in the National Health Checkup program in 2006. The amount of glucocorticoids prescribed was calculated based on the defined daily dose (DDD). The total DDD was obtained by adding oral and parenteral glucocorticoids for 6 months from the index date. Subjects were categorized into four groups according to total glucocorticoid DDDs: non-users (DDDs=0), low users (0< DDDs ≤45), intermediate users (45< DDDs ≤90), and high users (90< DDDs). We followed them for 2 years. A multivariate Cox proportional hazard model was used to evaluate the effects of the total amount of glucocorticoid use on hip and vertebral fractures.
Results
Higher glucocorticoid use was associated with a higher risk of vertebral fracture. Relative to non-users, the vertebral fracture risk was 1.39 times higher in the low-user group, 1.94 times higher in the intermediate-user group, and 2.43 times higher in the highuser group. The risk of hip fracture was 1.72 times higher in intermediate users and 3.28 times higher in high users than in non-users.
Conclusion
As the amount of glucocorticoid use for 6 months increased, the risk of hip and vertebral fractures became higher. In order to prevent fractures, it is necessary for doctors to evaluate the total amount of glucocorticoid prescribed to the patient and to provide appropriate treatment.

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Average daily glucocorticoid dose, number of prescription days, and cumulative dose in the initial 90 days of glucocorticoid therapy are associated with subsequent hip and clinical vertebral fracture risk: a retrospective cohort study using a nationwide h
Masayuki Iki, Kenji Fujimori, Shinichi Nakatoh, Junko Tamaki, Shigeyuki Ishii, Nobukazu Okimoto, Hironori Imano, Sumito Ogawa
Osteoporosis International.2024; 35(5): 805. CrossRef
Chronic airway disease as a major risk factor for fractures in osteopenic women: Nationwide cohort study
Sung Hye Kong, Ae Jeong Jo, Chan Mi Park, Kyun Ik Park, Ji Eun Yun, Jung Hee Kim
Frontiers in Endocrinology.2023;[Epub] CrossRef
Bad to the bones: prescribing of drugs for the prevention and treatment of osteoporosis in patients on chronic glucocorticoids
Sarah J. Billups, Vinh K Thai, Jacob Denkins, Ian C. Dettman, Micol S. Rothman
Archives of Osteoporosis.2023;[Epub] CrossRef
High Risk of Fractures Within 7 Years of Diagnosis in Asian Patients With Inflammatory Bowel Diseases
Hyung Jin Ahn, Ye-Jee Kim, Ho-Su Lee, Jin Hwa Park, Sung Wook Hwang, Dong-Hoon Yang, Byong Duk Ye, Jeong-Sik Byeon, Seung-Jae Myung, Suk-Kyun Yang, Beom-Jun Kim, Sang Hyoung Park
Clinical Gastroenterology and Hepatology.2022; 20(5): e1022. CrossRef
Challenges in the diagnosis and management of glucocorticoid‐induced osteoporosis in younger and older adults
Madhuni Herath, Bente Langdahl, Peter R. Ebeling, Frances Milat
Clinical Endocrinology.2022; 96(4): 460. CrossRef
Comparative effectiveness of bisphosphonate treatments for the prevention of re-fracture in glucocorticoid-induced osteoporosis: protocol for a systematic review and meta-analysis
Hongmin Chu, Bo-Hyoung Jang, GaYoon Kim, Seowoo Bae, Hyeju Lee, Seonghee Nam, Jeonghoon Ahn
BMJ Open.2022; 12(9): e062537. CrossRef
Why Do We Need Proactive Management for Fracture Prevention in Long-Term Glucocorticoid Users?
Han Seok Choi
Endocrinology and Metabolism.2020; 35(3): 549. CrossRef

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